Process for preparing tamsulosin

ABSTRACT

The present invention relates to a process for preparing Tamsulosin, an anti-benign prostatic hyperplasia drug, which comprises converting o-ethoxyphenoxyethanol to a corresponding sulfonate, and reacting the sulfonate with (R)-(−)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide by condensation to produce Tamsulosin.

FIELD OF THE INVENTION

The present invention relates to a process for preparing Tamsulosin, an anti-benign prostatic hyperplasia drug.

DESCRIPTION OF THE PRIOR ART

The chemical name of Tamsulosin is (R)-(−)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide hydrochloride, with the following structural formula (1):

Tamsulosin is a selective antagonist of α_(1c)-receptor, which was clinically used for treating hypertension initially, and now is mainly used for treating benign prostatic hyperplasia. Tamsulosin was developed by Yamanouchi Pharmaceutical Co., Ltd. of Japan and firstly commercialized in Japan in 1996. Yamanouchi Pharmaceutical Co. Ltd. owns a patent, EP 0 034 432 (published on Aug. 26, 1981), for Tamsulosin.

EP 0 034 432 to Imai et al. discloses a synthetic route of Tamsulosin as follows:

EP 0 257 787 to Okada et al. (published on Mar. 2, 1988) and U.S. Pat. No. 4,731,478 to Niigata et al. (published on Mar. 15, 1988) disclose that Tamsulosin is prepared, with a yield of approximately 40%, by condensation of R-(−)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide with 1-bromo-2(o-ethoxyphenoxy)ethane. The synthetic route is as follows:

J of Labeled Compounds and Radiopharmaceuticals(I), 171 (1988) by William J. Wheler discloses that Tamsulosin is prepared by condensation of 2-(2-ethoxyphenoxy)-acetaldehyde with R-(−)-5(2-aminopropyl)-2-methoxybenzenesulfonamide and followed by reduction. In the reaction, the use of 5% Pd/C can obtain a reduction yield of 32.8%, and the use of NaBH₃CN can obtain a reduction yield of 57.2%. The synthetic route is as follows:

WO 03/037850 A1 to Hoorn et al. (published on May 8, 2003) discloses that Tamsulosin is prepared by condensation of 2-methoxy-5-(2-oxopropyl)-5 benzenesulfonamide with 2-(2-ethoxyphenoxy)-1-ethanamine and followed by reduction to afford DL-Tamsulosin, which is then salified with (+)camphor-10-sulphonic acid, resolved into individual optical isomers, and then recrystallized four times to produce Tamsulosin, with a yield of 8.9%. The synthetic route is as follows:

SUMMARY OF THE INVENTION

The present invention relates to a novel process for preparing Tamsulosin, which includes reacting o-ethoxyphenoxyethanol with sulfonyl chloride to produce a sulfonate, and then condensating the resulted sulfonate with an optically active amine, (R)-(−)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide to produce Tamsulosin. The synthetic route is as follows:

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel process for preparing Tamsulosin, which includes reacting o-ethoxyphenoxyethanol with sulfonyl chloride to produce a sulfonate, and then condensating the resulted sulfonate with an optically active amine, (R)-(−)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide to produce Tamsulosin. The synthetic route is as follows:

Specifically, the process of the present invention includes the following two steps: (i) reacting o-ethoxyphenoxyethanol (compound (2)) with sulfonyl chloride of Formula RSO₂Cl to produce o-ethoxyphenoxyethanol sulfonate (compound (3)), wherein R is (C₁-C₆)alkyl, such as methyl and ethyl, or phenyl substituted by halogen, nitro and/or (C₁-C₆)alkyl (such as methyl), preferably substituted at the ortho, para, or meta position; and (ii) reacting the compound (3) with (R)-(−)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide (compound (4)) with a suitable organic amine and/or inorganic base as an acid scavenger at a temperature of about 40 to 100° C., in the presence of a catalyst and a suitable solvent, to prepare Tamsulosin.

The detailed reaction steps and conditions are described as follows:

Step (i):

The compound (2) is dissolved into an organic solvent (the suitable solvent is selected from the group consisting of chloromethane (preferably dichloromethane and/or trichloromethane), chloroethane (preferably dichloroethane), benzene, substituted benzene (preferably toluene), pyridine, other similar organic solvents and mixtures thereof, stirred until they are fully dissolved, and cooled to about −10 to 10° C., preferably about −5 to 5° C., more preferably about −5 to 0° C. Then, sulfonyl chloride of Formula RSO₂Cl (wherein R is (C₁-C₆)alkyl, such as methyl and ethyl, or phenyl substituted by halogen, nitro and/or (C₁-C₆)alkyl (such as methyl), preferably substituted at the ortho, para, and meta position) is added dropwise into the mixture. After addition, the reaction is carried out at a temperature of about 0 to 10° C., preferably about 0 to 5° C., until the compound (2) disappears. The reacting solution is gradually added into ice water to isolate white solids, which are then filtered, washed and dried to obtain the corresponding sulfonate (compound (3)), with a yield of 65-90%. Step (ii)

The compound (3), an organic amine and/or inorganic base as an acid scavenger, a catalyst and a suitable solvent are added into a reaction flask and heated to about 40-50° C., and then the compound (4) is added in portions; wherein the organic amine as an acid scavenger is selected from the group consisting of an organic tertiary amine, pyridine and mixtures thereof, preferably the group consisting of triethylamine, pyridine and mixtures thereof; and the inorganic base as an acid scavenger is selected from the group consisting of KOH, NaOH, K₂CO₃, NaHCO₃, the like and mixtures thereof; the catalyst is selected from the group consisting of monovalent inorganic iodides, preferably the group consisting of potassium iodide (KI), sodium iodide (NaI), copper iodide (CuI) and mixtures thereof; the proper solvent is an aprotic organic solvent, preferably selected from the group consisting of N,N-dimethylformamide (DMF), dimethyl sulphoxide (DMSO), N,N-dimethylacetamide (DMAC), the like and mixtures thereof. After the addition of the compound (4), the reaction mixture is heated at a temperature of about 50-100° C., preferably about 50-80° C., more preferably about 55-65° C., until the compound (3) disappears. Then, the mixture is cooled to room temperature, added with water, extracted with ethyl acetate or the like, distilled off the solvent under reduced pressure, and added with an organic solvent containing HCl (preferably selected from the group consisting of ethyl acetate-HCl, CH₃OH—HCl, EtOH—HCl, (CH₃)₂CHOH—HCl and mixtures thereof) to isolate white solids, which are then recrystallized with an aqueous methanol, various aqueous, alcohols, acetone, or dissolvants of above in mixure with ethyl acetate, methyl tert-butyl ether, benzene and/or toluene to produce Tamsulosin, with a yield of 55-70%.

EXAMPLES Example 1 o-ethoxyphenoxyethanol-methylsulfonate

50.0 g (0.28 mol) o-ethoxyphenoxyethanol and 197 g pyridine are added into a reaction flask, stirred until they are fully dissolved, and then cooled to −5 to 0° C. During stirring, 53.1 g (0.46 mol) methyl sulfonyl chloride is added gradually into the flask at a temperature controlled at −5 to 0° C. After addition, the reaction lasts for 3 to 4 hours at a temperature of 0 to 5° C. After the reaction is complete, the reacting solution is added gradually into 350 ml ice water under stirring at a temperature controlled at 0 to 5° C. to isolate gradually white solids, which are then filtered, and the filter cake is rinsed three times with 150 ml water until there is no smell of pyridine, and then dried to obtain 61.9 g title compound. Yield: 85.0%; purity: 99.83% (HPLC).

Example 2 (R)-(−)-5-[2-[(2-ethoxyphenoxy)ethyl]amino]-propyl-2-methoxybenzenesulfonamide hydrochloride (Tamsulosin)

27.7 g (0.11 mol) o-ethoxyphenoxyethanol-methylsulfonate, 20.0 g (0.082 mol) R-(−)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide, 7.5 g (0.09 mol) NaHCO₃, 1.36 g potassium iodide (KI) and 80 ml dimethylformamide (DMF) are placed into a reaction flask, which is supplied with N₂, heated to 55 to 65° C. and reacted for 11 hours. After the reaction is complete, the reacting solution is cooled to room temperature, added with 600 ml water, and extracted three times with 500 ml ethyl acetate. Then, the ethyl acetate extract solutions are combined, rinsed twice with 100 ml water, dried with anhydrous magnesium sulfate, and distilled off ethyl acetate under reduced pressure. After that, the residue is dissolved in ethanol and filtered while it is still warm. The filtrate is cooled to room temperature, and EtOH—HCl is added gradually until the filtrate has a pH of 2. White solids are isolated. Thereafter, the solids are recrystallized with aqueous ethanol to isolate white crystals, which are then filtered, washed with ethanol, and dried to obtain 20.4 g title compound. Yield: 56.9%. 

1. A process for preparing Tamsulosin, which comprises the following step: reacting o-ethoxyphenoxyethanol sulfonate of Formula (3) with R-(−)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide of Formula (4) at a temperature of about 40 to 100° C. by condensation to produce Tamsulosin:

wherein R is (C₁-C₆)alkyl or phenyl substituted by halogen, nitro and/or (C₁-C₆)alkyl.
 2. The process according to claim 1, wherein said reaction is conducted at a temperature of about 50 to 80° C.
 3. The process according to claim 2, wherein said reaction is conducted at a temperature of about 55 to 65° C.
 4. The process according to claim 1, wherein said reaction is conducted in the presence of a solvent.
 5. The process according to claim 4, wherein said solvent is an aprotic organic solvent.
 6. The process according to claim 4, wherein said solvent is selected from the group consisting of N,N-dimethylformamide (DMF), dimethyl sulphoxide (DMSO), N,N-dimethylacetamide (DMAC) and mixtures thereof.
 7. The process according to claim 1, wherein an acid scavenger is used in the reaction.
 8. The process according to claim 7, wherein said acid scavenger is an organic amine, an inorganic base or combinations thereof.
 9. The process according to claim 8, wherein said organic amine is selected from the group consisting of an organic tertiary amine, pyridine and mixtures thereof.
 10. The process according to claim 9, wherein said organic amine is selected from the group consisting of triethylamine, pyridine and mixtures thereof.
 11. The process according to claim 8, wherein said inorganic base is selected from the group consisting of KOH, NaOH, K₂CO₃, NaHCO₃ and mixtures thereof.
 12. The process according to claim 1, wherein said reaction is conducted in the presence of a catalyst.
 13. The process according to claim 12, wherein said catalyst is a monovalent inorganic iodide.
 14. The process according to claim 12, wherein said catalyst is selected from the group consisting of potassium iodide (KI), sodium iodide (NaI), copper iodide (CuI) and mixtures thereof.
 15. A process for preparing o-ethoxyphenoxyethanol sulfonate, which comprises the following step: reacting o-ethoxyphenoxyethanol of Formula (2) with sulfonyl chloride of Formula RSO₂Cl at a temperature of about −10 to 10° C., to produce o-ethoxyphenoxyethanol sulfonate of Formula (3),

wherein R is (C₁-C₆)alkyl or phenyl substituted by halogen, nitro and/or (C₁-C₆)alkyl.
 16. The process according to claim 15, wherein said reaction is conducted at a temperature of about −5 to 5° C.
 17. The process according to claim 16, wherein said reaction is conducted at a temperature of about 0 to 5° C.
 18. The process according to claim 15, wherein said reaction is conducted in the presence of a solvent.
 19. The process according to claim 18, wherein said solvent is selected from the group consisting of chloromethane, chloroethane, benzene, substituted benzene, pyridine and mixtures thereof.
 20. The process according to claim 19, wherein said solvent is selected from the group consisting of dichloromethane, trichloromethane, dichloroethane, benzene, toluene and mixtures thereof.
 21. A process for preparing Tamsulosin, which sequentially comprises the following steps: (i) reacting o-ethoxyphenoxyethanol of Formula (2) with sulfonyl chloride of Formula RSO₂Cl at a temperature of about −10 to 10° C., to form o-ethoxyphenoxyethanol sulfonate of Formula (3);

and (ii) reacting o-ethoxyphenoxyethanol sulfonate of Formula (3) with R-(−)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide of Formula (4) at a temperature of about 40 to 100° C. by condensation to produce Tamsulosin;

wherein R is (C₁-C₆)alkyl or phenyl substituted by halogen, nitro and/or (C₁-C₆)alkyl.
 22. The process according to claim 21, wherein said step (i) is conducted at a temperature of about −5 to 5° C.
 23. The process according to claim 22, wherein said step (i) is conducted at a temperature of about 0 to 5° C.
 24. The process according to claim 21, wherein the step (i) is conducted in the presence of a solvent.
 25. The process according to claim 24, wherein said solvent is selected from the group consisting of chloromethane, chloroethane, benzene, substituted benzene, pyridine and mixtures thereof.
 26. The process according to claim 25, wherein said solvent is selected from the group consisting of dichloromethane, trichloromethane, dichloroethane, benzene, toluene and mixtures thereof.
 27. The process according to claim 21, wherein said step (ii) is conducted at a temperature of about 50 to 80° C.
 28. The process according to claim 27, wherein said step (ii) is conducted at a temperature of about 55 to 65° C.
 29. The process according to claim 21, wherein said step (ii) is conducted in the presence of a solvent.
 30. The process according to claim 29, wherein said solvent is an aprotic organic solvent.
 31. The process according to claim 29, wherein said solvent is selected from the group consisting of N,N-dimethylformamide (DMF), dimethyl sulphoxide (DMSO), N,N-dimethylacetamide (DMAC) and mixtures thereof.
 32. The process according to claim 21, wherein an acid scavenger is used in step (ii).
 33. The process according to claim 32, wherein said acid scavenger is an organic amine, an inorganic base or combinations thereof.
 34. The process according to claim 33, wherein said organic amine is selected from the group consisting of an organic tertiary amine, pyridine and mixtures thereof.
 35. The process according to claim 34, wherein said organic amine is selected from the group consisting of triethylamine, pyridine and mixtures thereof.
 36. The process according to claim 33, wherein said inorganic base is selected from the group consisting of KOH, NaOH, K₂CO₃, NaHCO₃ and mixtures thereof.
 37. The process according to claim 21, wherein said step (ii) is conducted in the presence of a catalyst.
 38. The process according to claim 37, wherein said catalyst is a monovalent inorganic iodide.
 39. The process according to claim 37, wherein said catalyst is selected from the group consisting of: potassium iodide (KI), sodium iodide (NaI), copper iodide (CuI) and mixtures thereof. 